The broad objective of this proposal is to investigate the interrelation of insulin and somatomedin in the pathogenesis of diabetes mellitus. Poor growth and osteopenia are common problems of diabetes mellitus. Other complications have been related to the increased growth hormone (GH) responses in diabetics because GH is diabetogenic and may be one causal factor in diabetic retinopathy. Although GH levels are elevated in diabetes mellitus, the plasma activity of somatomedin (SM) has been reported to be low. The low plasma activity of SM may therefore explain the poor growth and bone formation of diabetics in view of the evidence that SM mediates the effect of GH on growth and bone formation. Since SM may be the feedback inhibitor of GH secretion, a low plasma activity of SM could also explain the elevated GH levels and the complications secondary to this. In addition to low plasma activity of SM observed in diabetic humans and animals, there is inconclusive evidence that insulin stimulates SM synthesis by the liver. We propose to study the effect of insulin on somatomedin synthesis by a new method developed in our laboratory. In preliminary experiments normal rat liver monolayer cell cultures have been shown to synthesize SM and to respond to GH. Insulin will be tested in this system using cells from normal, diabetic, hypophysectomized and hypophysectomized GH-treated rats. The requirement of insulin for various cofactors including thyroid hormone, cortisol and GH will be tested. Somatomedin radioreceptorassays will be used to measure SM synthesis. Using this cell culture method the mechanism of action of insulin in stimulating SM synthesis will be investigated to determine whether insulin acts by regulating gene transcription, processing and transfer of mRNA, translational events or post-translational events.